Ever since Miller in 1890 first provided evidence that acid produced by the oral bacteria during the fermentation of carbohydrates is mainly responsible for the demineralization of teeth and the initiation of the dental caries process, the ability to retard or prevent the demineralization of teeth has been extensively studied. Miller W. D. (1890) "Micro-organisms of the human mouth," Reprinted 1973. Karger, Basel. Miller described the formation of dental caries as a two step process. In the first step, oral bacteria, primarily Gram-positive bacteria, metabolize fermentable carbohydrates present in the oral cavity to produce acid. In the second step, the acids generated by the oral bacteria demineralize tooth enamel, dentine and/or cementum, thereby creating a caries lesion or cavity in the tooth crown or root.
The primary source of fermentable carbohydrates metabolized by the oral bacteria in the first step of the Miller process is the diet. Glucose is the main sugar available from dietary carbohydrates. It is a constituent monosaccharide of sucrose, maltose, lactose and starch. Studies on pure cultures of oral bacteria have shown that glucose is readily fermented by the Gram-positive bacteria which contribute far more to the fermentation process than oral Gram-negatives. Such fermentation can be arbitrarily classified as either homofermentative, where lactic acid is the main product, or heterofermentative, where substantial amounts of products other than lactic, including formic, acetic, propionic and succinic acids, as well as ethanol and carbon dioxide can be produced. Platt and Foster (1958) J. Bacteriol., 75:453-459.
Investigators have tried with varying degrees of success to reduce acid production by the microorganisms present in dental plaque. Jenkins G. N. (1978) The Physiology and Biochemistry of the Mouth, 4th Ed., Oxford, England, Blackwell, pp. 414-500. These have included methods that try to (i) reduce the availability of fermentable carbohydrate from the diet, (ii) reduce the amount of plaque and the number of acidogenic bacteria in dental plaque, (iii) interfere with specific bacteria, (iv) interfere with bacterial glycolysis, the metabolic process by which the plaque bacteria make acid from carbohydrates, (v) neutralize the acids formed during glycolysis, and (vi) stimulate formation of base by the plaque bacteria mainly from urea and arginine to counter the acid formation characteristic of the caries process. Kleinberg et al. (1979) "Metabolism of nitrogen by the oral mixed bacteria". In: Saliva and Dental Caries (Edited by Kleinberg et al.) pp.357-377, Information Retrieval, Washington D.C. These methods however, have had limited success in reducing dental caries.
Researchers have had greater success in reducing or preventing dental caries by combating the second step of the Miller dental caries formation process, namely, reducing the dissolution of enamel mineral by reducing the solubility of enamel using fluoride. Numerous studies have examined therapeutics which inhibit the dissolution of dental enamel by the acid generated by plaque bacteria. Fluoride has proven to be the most effective therapeutic. Newburn (1986)
Fluorides and Dental Caries, 3rd. Ed., Springfield, Ill., Charles Thomas. Fluoride has been found to inhibit the dissolution of enamel by dental plaque acids by reducing the rate of solubilization, increasing remineralization and altering the solubility product of the calcium phosphate that constitutes most of the mineral in enamel, cementum and dentine. To a much lesser degree, fluoride also affects bacterial transport of sugars and the glycolytic process. Hamilton (1969) Can. J. Microbiol., 15:1021-1027.
Although various therapeutic agents have been examined for their ability to prevent dental caries, the incidence of dental caries remains unacceptably high, particularly in third world countries and in individuals with saliva deficiencies, especially adults on saliva inhibiting medications. One reason for the failure of conventional therapeutics to adequately retard dental caries is that these dental therapeutics primarily focus on the second step of the Miller dental caries process and have failed to provide therapeutics that adequately address the fact that dental caries is a multi-factorial disease and needs a multi-factorial approach. Hence, it is not surprising that reduction of the solubility of tooth enamel using fluoride has resulted in a limited reduction in dental caries in a range of approximately 20% to 40%. Few attempts have been made to develop agents that can simultaneously affect both the acid production and the enamel demineralization processes.
The present invention alleviates many of the problems associated with current therapies for preventing dental caries. In particular, the oral compositions provided by the present invention combat the dental caries process at both stages described by Miller. Specifically, the cariostatic oral compositions described herein contain therapeutic amounts of calcium, arginine and a cariostatic anion. These compounds may interact to form an anti-caries complex.
Arginine favors the formation of base by the dental plaque bacteria and the proliferation of an alkali producing microflora in plaque. Kanapka and Kleinberg (1983) Archs. oral Biol. 28, 1007-1015. The acids produced by many of the plaque bacteria are neutralized by the alkali compounds produced from arginine, whether or not the amino acid is found free or becomes available from peptides or proteins, especially from saliva. Kleinberg et al. (1979) "Metabolism of nitrogen by the oral mixed bacteria" In: Saliva and Dental Caries (Edited by Kleinberg et al.) pp. 357-377, Information Retrieval, Washington, D.C. Thus, the arginine component of the composition described herein attacks the first stage of the Miller process.
Calcium is another component of the oral compositions of the invention. Calcium suppresses the solubilization of tooth enamel by mass action and reduces the release of calcium from tooth enamel when attacked by acid. Calcium precedes the release of phosphate from enamel, dentine and other calcium phosphate containing tissues during acid solubilization. Thus, the calcium component of the composition described herein attacks the second stage of the Miller caries process.
The cariostatic anions of the oral compositions of the present invention may attack both stages of the caries process. Cariostatic anions may (i) provide buffering which enhance the acid neutralizing activity of the arginine as well as neutralizing the acid itself, (ii) provide an organic phosphate source to act as a surface covering or "poison" or to be hydrolyzed by the plaque bacteria to release inorganic orthophosphate which inhibits tooth dissolution and enhances tooth remineralization or (iii) do both. Unlike conventional oral compositions, the oral compositions described by the present invention contain components that are coordinated to significantly reduce dental caries by attacking the formation of caries lesions at both steps of the Miller caries formation process.